The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a high-molecular-weight protein complex in the cytoplasm, is composed of three core components: the sensor protein NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and the effector protein caspase-1. It plays a critical role in regulating host immune and inflammatory responses. Studies have shown that the NLRP3 inflammasome has increasingly become a focal point in tumor molecular biology field. A growing body of evidence indicates that the increased expression and activation of the NLRP3 inflammasome is closely associated with the pathogenesis of head and neck squamous cell carcinoma (HNSCC) and the tumor microenvironment (TME). It may promote tumor proliferation, invasion, migration, and other biological behaviors through various regulatory mechanisms while influencing tumor immune evasion and therapy resistance, which holds promise as a prognostic biomarker for patients. This review explores the current effect and mechanism of the NLRP3 inflammasome and its signaling pathways in head and neck cancer, providing insights into clinical targeted drug development and molecular immunotherapy.
Humans ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Inflammasomes/metabolism* ; Head and Neck Neoplasms/pathology* ; Squamous Cell Carcinoma of Head and Neck/metabolism* ; Tumor Microenvironment ; Signal Transduction ; Animals

Osteoarthritis (OA) causes chronic pain that significantly impairs quality of life, with current treatments often proving insufficient and accompanied by adverse effects. Recent research has identified the dorsal root ganglion (DRG) and its resident macrophages as crucial mediators of chronic OA pain through neuroinflammation driven by macrophage polarization. We present a novel injectable thermo-sensitive hydrogel system, KAF@PLEL, designed to deliver an anti-inflammatory peptide (KAF) specifically to the DRG. This biodegradable hydrogel enables sustained KAF release, promoting the reprogramming of DRG macrophages from pro-inflammatory to anti-inflammatory phenotypes. Through comprehensive in vitro and in vivo studies, we evaluated the hydrogel's biocompatibility, effects on macrophage polarization, and therapeutic efficacy in chronic OA pain management. The system demonstrated significant capabilities in preserving macrophage mitochondrial function, suppressing neuroinflammation, alleviating chronic OA pain, reducing cartilage degradation, and improving motor function in OA rat models. The sustained-release properties of KAF@PLEL enabled prolonged therapeutic effects while minimizing systemic exposure and side effects. These findings suggest that KAF@PLEL represents a promising therapeutic approach for improving outcomes in OA patients through targeted, sustained treatment.

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug dis-covery.In the present study,we used a mass spectrometry(MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds.The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells.Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol,as well as the noncanonical targets of clinically approved tamoxifen,lovastatin,and their derivatives.Furthermore,the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints.This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

Objective:To discuss the anti-inflammatory and antioxidant effect of mesalazine(MSZ)in the RAW264.7 cell model,and to elucidate its therapeutic effect on periodontitis in the rats.Methods:The proliferation rates of RAW264.7 cells stimulated by different concentrations(0,62.5,125.0,250.0,500.0,1 000.0,and 2 000.0 mg·L-1)of MSZ were detected by CCK-8 method to determine the optimal concentration of MSZ for cell treatment.Porphyromonas gingivalis lipopolysaccharide(P.g-LPS)and MSZ were used to treat the RAW264.7 cells,and the cells were divided into control group,P.g-LPS group,and MSZ+P.g-LPS group.The levels of reactive oxygen species(ROS)in the cells in various groups were detected by the DCFH-DA fluorescent probe assay;the malondialdehyde(MDA)levels,glutathione(GSH)levels and superoxide dismutase(SOD)activities in the cells in various groups were detected by ELISA method;the expression levels of inflammatory factors interleukin-8(IL-8)and interleukin-1β(IL-1β)mRNA in the cells in various groups were detected by real-time fluorescence quantitative PCR(RT-qPCR)method.The periodontitis rat model was established by the ligation method combined with the injection of P.g bacterial fluid.A total of 18 rats were randomly divided into control group(without treatment),model group(making period ontits model),and drug administration group(making periodontits model and given MSZ),and there were 6 rats in each group.Micro-CT was used to assess the alveolar bone destruction of the rats in various groups;HE staining was used to observe the morphology of periodontal tissue of the rats in various groups.Results:Compared with control group,the proliferation rate of the cells in 500.0 mg·L-1 MSZ group was significantly increased(P＜0.01),so 500.0 mg·L-1 MSZ was subsequently selected to treat the cells.Compared with control group,the levels of ROS and MDA in the cells in P.g-LPS group were significantly increased(P＜0.01),and the level of GSH and activity of SOD were significantly decreased(P＜0.01),and the expression levels of IL-1β and IL-8 mRNA were significantly increased(P＜0.01);compared with P.g-LPS group,the levels of ROS and MDA in the cells in MSZ+P.g-LPS group were significantly decreased(P＜0.01),the level of GSH and activity of SOD were significantly increased(P＜0.01),and the expression levels of IL-1β and IL-8 mRNA were significantly decreased(P＜0.01).The micro-CT assay results showed that compared with control group,the distance from the cemento-enamel junction to alveolar bone crest(CEJ-ABC)of the rats in model group was significantly increased(P＜0.01),and the bone volume fraction(BV/TV)was significantly decreaced(P＜0.05);compared with model group;the CEJ-ABC of the rats in drug administration group was decreased(P＜0.01),and the BV/TV was increased(P＜0.05).The HE staining results showed that the inflammatory cell infiltration in periodontal tissue of the rats in drug administration group was reduced,and epithelial attachment was restored.Conclusion:MSZ effectively inhibits the production of pro-inflammatory factors and peroxides in the P.g-LPS-induced RAW264.7 cells,improves the cellular anti-inflammatory and antioxidant capacity,inhibits the alveolar bone resorption,and alleviates the inflammation of periodontal tissues in the periodontitis rats.

Objective:To translate the Cumulated Ambulation Score (CAS) into Chinese and test its reliability and validity in elderly inpatients, to provide a basis for assessing elderly inpatients′ basic mobility during hospitalization.Methods:This was a cross-sectional study. After obtaining the authorization of the original author, the Chinese version of CAS was formed by WHO′s cross-cultural translation process. A total of 414 hospitalized elderly inpatients from Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, and Shanghai Yangpu District Kongjiang Hospital were selected between March and September 2021. Cronbach′s α coefficient was used to test internal consistency, linear weighted Kappa was employed to assess inter-rater reliability, and concurrent validity was examined using items related to mobility of Barthel Index scores as a reference standard.Results:Of the 414 patients, 221 were males and 193 were females, and the patients aged (76.67 ± 9.98) years old; 122 cases (29.5%) had a perfect score of 6 with normal basic mobility, 89 cases (21.5%) had a score of 0 with complete loss of mobility, and the remaining 203 patients had a score of 1-5 with varying degrees of reduced mobility. The Chinese version of CAS demonstrated good assessment performance for basic mobility in elderly inpatients with a Cronbach′s α coefficient of 0.952. Weighted Kappa values for individual items and total scores showed excellent agreement among raters (>0.85), while concurrent validity yielded a value of 0.935 ( P<0.01) when compared with Barthel Index scores.Total score of CAS was significantly correlated with item scores and total score of Barthel index ( r values were 0.423 to 0.944, all P<0.01). Conclusions:The Chinese version of CAS has good reliability and validity. The items are concise, clear and easy to understand. It is suitable as a preliminary screening tool for clinical departments to evaluate the basic mobility of elderly inpatients.

Objective To study the effects of radiation on the morphology,function,and NLRP3 expression of mouse salivary gland tissue,and provide new ideas to repair radiation-induced damage to salivary gland tissue.Methods We established a mouse model of radiation-induced submandibular gland injury and Recorded the weight of drinking water.The salivary flow rate was assessed,and HE staining was used to observe submandibular gland injury.Immunohistochemistry and Real-time PCR were used to assess expression of NLRP3 and Caspase-1 in the radiation-injured submandibular gland of mice at 1,3,7 and 14 days after radiation exposure.Results Over time,the amount of water consumed by radiation group mice was gradually increased,the salivary flow rate was decreased,and inflammatory cells in the submandibular gland continued to increase.Acinar cells gradually showed lesions,such as nuclear pyknosis and vacuolization.At 7 and 14 days after radiation exposure,expression levels of NLRP3 and Caspase-1 proteins and genes in the radiation group were significantly higher than those in the normal group(P＜0.05).Conclusions Radiation damages mouse submandibular gland tissue and activates the NLRP3 inflammasome to increase its expression level.

Objective To explore the value of machine learning(ML)models based on non-contrast CT(NCCT)radiomics features for predicting the severity of acute phase traumatic brain injury(TBI).Methods Totally 600 TBI patients were retrospectively collected as observation group,other 65 TBI patients were taken as external validation set,while 50 TBI patients were prospectively enrolled as prospective validation set.Patients in observation group were divided into high-risk subgroup(n=240)and low-risk subgroup(n=360)according to Glasgow outcome scale(GOS)at discharge.The severity of acute phase TBI in observation group was assessed by doctor A and B with the same criteria,then an artificial model was established based on clinical and NCCT data at the time of first diagnosis using logistic regression(LR)method for predicting the severity of acute phase TBI.Patients in observation group were divided into training set(n=420,including 168 in high-risk subgroup and 252 in low-risk subgroup)and test set(n=180,including 72 in high-risk subgroup and 108 in low-risk subgroup)at the ratio of 7∶3.Based on NCCT of training set,radiomics features were extracted and selected,and LR,support vector machine(SVM),random forest(RF)and K-nearest neighbor(KNN)were used to establish 4 ML models.The efficacies of the above models were validated in test set,external validation set(including 34 cases of high-risk and 31 cases of low-risk TBI)and prospective validation set(including 21 cases of high-risk and 29 cases of low-risk TBI),respectively.Results The area under the curve(AUC)of doctor A and B for evaluating the severity of acute phase TBI in observation group was 0.606 and 0.771,respectively,of artificial model was 0.824.Based on NCCT in training set,6 optimal radiomics features were selected to construct LR,SVM,RF and KNN ML models,with AUC of 0.983,0.971,0.970 and 0.984 in test set,respectively,while the AUC of artificial model was 0.708.The AUC of LR,SVM,RF,KNN ML models and artificial model in external validation set was 0.879,0.881,0.984,0.863 and 0.733,while in prospective validation set was 0.984,0.873,0.982,0.897 and 0.704,respectively.Conclusion ML models based on CT radiomics could effectively predict the severity of acute phase TBI.

Background/Aims: The shortage of donor liver hinders the development of liver transplantation. This study aimed to clarify the poor outcomes of functionally marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) after FML transplantation. Methods: Propensity score matching was used to control for confounding factors. The outcomes of the control group and FML group were compared to demonstrate the negative impact of FMLs on liver transplantation patients. We compared the clinical improvements of the different surgical types. To elucidate the underlying mechanism, we conducted bioinformatic analysis based on transcriptome and single-cell profiles. Results: FMLs had a significantly greater hazard ratio (HR: 1.969, P=0.018) than did other marginal livers. A worse 90-day survival (Mortality: 12.3% vs. 5.0%, P=0.007) was observed in patients who underwent FML transplantation. Patients who received FMLs had a significant improvement in overall survival after IFLT (Mortality: 10.4% vs 31.3%, P=0.006). Pyroptosis and inflammation were inhibited in patients who underwent IFLT. The infiltration of natural killer cells was lower in liver grafts from these patients. Bulk transcriptome profiles revealed a positive relationship between IL-32 and Caspase 1 (R=0.73, P=0.01) and between IL-32 and Gasdermin D (R=0.84, P=0.0012). Conclusions FML is a more important negative prognostic parameter than other marginal liver parameters. IFLT might ameliorate liver injury in FMLs by inhibiting the infiltration of NK cells, consequently leading to the abortion of IL-32, which drives pyroptosis in monocytes and macrophages.

OBJECTIVE: To investigate the role of the SIRT1/NF-κB pathway in mediating the effect of puerarin against lipopolysaccharide (LPS)-induced acute kidney injury (AKI). METHODS: Fifteen BALB/C mice were randomized into control group, LPS group and puerarin treatment group, and in the latter two groups, the mice were given an intraperitoneal injection of LPS (5 mg/kg), followed by daily injection of normal saline for 3 days or injection of puerarin (25 mg/kg) given 1 h later and then on a daily basis for 3 days. On day 5 after modeling, the kidney tissues were taken for histological observation and detection of cell apoptosis. The renal function indexes including urea nitrogen (BUN), serum creatinine (Scr) and kidney injury molecule 1 (KIM-1) and the levels of tumor necrosis factor (TNF-α) and interleukin 1β (IL-1β) were measured, and the expressions of SIRT1 and NF-κB-p65(acetyl K310) in the renal tissues were detected. RESULTS: Intraperitoneal injection of LPS caused obvious glomerular capillary dilatation, hyperemia, renal interstitial edema, and renal tubular epithelial cell swelling and deformation in the mice. The mouse models of LPS-induced AKI also showed significantly increased renal tubular injury score and renal cell apoptosis (P < 0.01) with increased serum levels of BUN, Scr, KIM-1, TNF-α and IL-1β (P < 0.01), enhanced renal expressions of TNF-α, IL-1β and NF-κB p65(acetyl K310) (P < 0.01) and lowered renal expression of SIRT1 (P < 0.05). Treatment with puerarin effectively alleviated LPS-induced renal interstitial edema and renal tubular epithelial cell shedding, lowered renal tubular injury score (P < 0.01) and renal cell apoptosis rate (P < 0.01), and decreased serum levels of BUN, Scr, KIM, TNF-α and IL-1β (P < 0.01). Puerarin treatment significantly reduced TNF-α, IL-1β and NF-κB p65 (acetyl K310) expression in the renal tissue (P < 0.05) and increased SIRT1 expression by 17% (P < 0.05) in the mouse models. CONCLUSION Puerarin can effectively alleviate LPS-induced AKI in mice possibly by modulating the SIRT1/NF-κB signaling pathway.
Animals ; Mice ; Mice, Inbred BALB C ; NF-kappa B ; Lipopolysaccharides ; Sirtuin 1 ; Tumor Necrosis Factor-alpha ; Acute Kidney Injury ; Disease Models, Animal ; Edema

OBJECTIVE: To explore the design points of a three-dimensional (3D) printed customized cementless intercalary endoprosthesis with an intra-neck curved stem and to evaluate the key points and mid-term effectiveness of its application in the reconstruction of ultrashort bone segments in the proximal femur. METHODS: Between October 2015 and January 2021, 17 patients underwent reconstruction with a 3D printed-customized cementless intercalary endoprosthesis with an intra-neck curved stem. There were 11 males and 6 females, the age ranged from 10 to 76 years, with an average of 30.1 years. There were 9 cases of osteosarcoma, 4 cases of Ewing sarcoma, 2 cases of chondrosarcoma, 1 case of liposarcoma, and 1 case of myofibroblastoma. The disease duration was 5-14 months, with an average of 9.5 months. Enneking staging included 16 cases of stage ⅡB and 1 case of stage ⅢB. The distances from the center of the femoral head to the body midline and the acetabular apex were measured preoperatively on X-ray images. Additionally, the distances from the tip of the intra-neck curved stem to the body midline and the acetabular apex were measured at immediate postoperatively and last follow-up. The neck-shaft angle was also measured preoperatively, at immediate postoperatively, and at last follow-up. The status of osseointegration at the bone-prosthesis interface and bone growth into the prosthesis surface were assessed by X-ray films, CT, and Tomosynthesis-Shimadzu metal artefact reduction technology (T-SMART). The survival status of the patients, presence of local recurrence or distant metastasis, and occurrence of postoperative complications were assessed. The recovery of lower limb function was evaluated pre- and post-operatively using the Musculoskeletal Tumor Society (MSTS) scoring system, and pain relief was evaluated using the visual analogue scale (VAS) scores. RESULTS: The patient's femoral resection length was (163.1±57.5) mm, the remaining proximal femoral length was (69.6±9.3) mm, and the percentage of femoral resection length/total femoral length was 38.7%±14.6%. All 17 patients were followed up 25-86 months with an average of 58.1 months. During the follow-up, 1 patient died of lung metastasis at 46 months postoperatively, and the remaining 16 patients survived tumor-free. There was no complication such as periprosthetic infection, delayed incision healing, aseptic loosening, prosthesis fracture, or periprosthetic fracture. No evidence of micromotion or wear around the implanted stem of the prosthesis was detected in X-ray and T-SMART evaluations. There was no significant radiolucent lines, and radiographic evidence of bone ingrowth into the bone-prosthesis interface was observed in all stems. There was no significant difference in the distance from the tip of the curved stem to the body midline and the apex of the acetabulum at immediate postoperatively and last follow-up compared with the distance from the center of the femoral head to the body midline and the apex of the acetabulum before operation, respectively (P>0.05), and there was no significant difference in the above indexes between immediate postoperatively and last follow-up (P>0.05). The differences in the neck-shaft angle at various time points before and after operation were also not significant (P>0.05). At last follow-up, the MSTS score was 26.1±1.2 and the VAS score was 0.1±0.5, which were significantly improved when compared with those before operation [19.4±2.1 and 5.7±1.0, respectively] (t=14.735, P<0.001; t=21.301, P<0.001). At last follow-up, none of the patients walked with the aid of crutches or other walkers. CONCLUSION The 3D printed customized cementless intercalary endoprosthesis with an intra-neck curved stem is an effective method for reconstructing ultrashort bone segments in the proximal femur following malignant tumor resection. The operation is reliable, the postoperative lower limb function is satisfactory, and the incidence of complications is low.
Female ; Male ; Humans ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Femur/surgery* ; Lower Extremity ; Bone-Implant Interface ; Femur Head ; Artificial Limbs